J. Org. Chem., Vol. 39, No. 2, 1974 277
Communications
(7) (8)
(9) (10) (11) (12) (13) (14) (15) (16) (17)
(18) (19)
SOC., 95, 6867 (1973); also see R. K. Boeckman, Jr., J. Org. Chem., in press. H. 0. House, W. L. Respess, and G. M. Whitesides, J. Org. Chem., 31, 3128 (1966). Exceptional reactivity in DME has been previously noted for the aikylation of sodio maionates** and metalation by organolithium compounds:8b (a) H. D. Zook, T. J. Russo, E. F. Ferrand, and D. S. Stolz, J. Org. Chem., 33, 2222 (1968); (b) M. Schlosser, J. Organomet. Chom., 8, 9 (1967), and references cited therein. The reactivity difference is not simply due to solubility differences as the copper-lithium enoiate 2 was demonstrated to be soluble in ether. Tetramethylethylenediamine was itself being alkylated in this experiment: thus the stoichiometry is uncertain. H. A. Smith, B. J. L. Huff, W. J. Powers, and D. Caine, J. Org. Chem., 32, 2851 (1967); W . Cocker, T. B. H. McMurry, and E. R . Simmons, J. Chem. SOC., 3022 (1965). H. E. Uiery and J. H. Richards, J , Amer. Chem. SOC.,86, 3113 (1964). R. Cornubert and A. Maurel, Bull. SOC.Chim. Fr., 1515 (1931). R. E. Ireland and J. A. Marshall, J. Org. Chem., 27, 1615 (1962). C. Ainsworlh in "Organic Syntheses," Collect. Voi. iV, Wiley, New York, N. Y . , 1963, p 536. L. Bardou, J. Eiguero, and R. Jacquier, Bull. SOC. Chim. Fr., 289 (1967); I. Deutsch and K. Deutsch, Tetrahedron Lett., 1849 (1966). E. Piers and R. J. Keziere, Can. J. Chem., 47, 137 (1969); H. 0. House and W. F. Fischer, J. Org. Chem., 34,'3615 (1969). J. Rouzaud, G. Cauquii, L. Giral, and J . Crouzet, Bull. SOC. Chim. Fr., 4837 (1968). A. P. Sloan Foundation Fellow, 1971-1973.
1530, 1300, 1250 cm-1; nmr (CDCl3) 6 8.2 (d, 1, NH), 7.8 (s, 1, NH), m at 7.2 (5, phenyl), 5.95 (dd, 1, J1 = 5, JZ = 10 Hz, H-6), 5.25 (d, 1, J = 5 Hz, H-5), 4.55 (s, 2, CH2), 3.75,3.95 (overlapping s, 3, CHz,OH), 1.4, 1.3 (s,6, CH3). In a model reaction, compound 4 reacted with thiopheno1 in the presence of triethylamine to give a mixture of cis and trans (1: 1) 3-(phenoxyacetamido)-4-phenylthio-2azetidinone (6): 80%; ir (KBr) 3380, 1763, 1655, 1600, 1540; nmr (acetone-&) S 8.1 (br s, 1, NH), m at 7.2 (11,aromatic and solvate), 5.65 (dd, Ih, J1 = 5, J z = 10 Hz, H-3 cis), 5.4 (d, l/2, J = 5 Hz, H-4 cis), 5.2 (d, I/2, J = 2 Hz, H-4 trans), 4.8 (m, Ih, H-3 trans), 4.6 (2s, 2, CHz). Azetidinones in which the nitrogen is substituted (7)do not react with mercaptans under these conditions. Also, if the mercaptan is sterically bulky the reaction is slow and the competing epimerization of H-4 becomes the dominant reaction route. Compound 5 reacted with isobutylmercaptan only very slowly (4 days) to give 3-(phenoxyacetamido)-4-trans-isobutylthio-2-azetidinone. tert-Butyimercaptan did not give the desired product at all; instead trans-5 was isolated.
rn"?....aNHp N
Department of Chemistry University of Illinois Urbana, Illinois 61801
Robert M. Coates*l9 Louise Ofenshain Sandefur
Received October 16, 1973
0
0
NH
0
H R
CH,OH
5
2, R = CO,H 3, R = NCO 4, R = -OH
7, R = CO,CH,CH(CHJZ
The Removal and Displacement of the Thiazolidine Ring in Penici1lin.l IV. Formation of a Biologically Active Cephem System
Summary: The thiazolidine ring of penicillin V (1) has been removed and replaced by a cephem system.
9
6, R = SPh
8,R=S Sir: The thiazolidine ring of penicillins has been displaced for the case of 6-[2-'methyl-2-(o-nitrophenoxy)propionamiCH,OH do]penicillanic acid2 and phthalimidopenicillanic acid.1 We now wish to report the extension of this displacement reaction to 6-phenoxyacetylaminopenicillanic acid (penicillin V, 1). Penicillin V (1) was oxidized to the sulfone Z3 using neutral aqueous permanganate: mp 149-151"; 94%; ir (KBr) 3450, 1800, 1735, 1675, 1600, 1530, 1325, 1240 cm-l; 6H H nmr (acetone-&) 6 8.0 (d, 1, NH), 7.1 (m, 5, phenyl), 6.1 9 (dd, 1, J1 = 5, Jz = 11 Hz, H-6), 5.1 (d, 1,J = 5 Hz, H-5), Reaction of 5 with o-mercaptobenzyl alcohol in the 4.55 (s, 2, CH2), 4.4 (s, 1, CHI, 1.5, 1.3 (s, 6, CH3). The presence of triethylamine gave cis and trans (1:l) 3sulfone 2 was converted to the isocyanate 3 via the mixed (phenoxyacetamido)-4-(2- hydroxymethylphenylthio) -2anhydride using ethyl chloroformate and pyridine, folazetidinone (8): 78%; ir (CH2ClZ) 3300, 1755, 1690, 1540, lowed by treatment with sodium azide and thermal rear1500 cm-1; nmr (acetone-&) 6 8.7-6.9 (m, NH and arorangement. The use of triethylamine with the penicillin V matic, 11), 5.75 (dd, lh, J1 = 5, JZ= 8 Hz, H-3 cis), 5.4 side chain resulted in reduced yields of the isocyanate (d, 1/2, J = 5, H-4 cis), 5.2 (d, I,, J = 2, Hq trans), 4.9 (2s, owing to loss of the P-lactam. Hydrolysis of the isocyanate 2, CHz), 4.7 ( 2 ~ 2, , CHz), 4.4 (dd, Yz, Ji = 2, Jz = 7 Hz, afforded the "aldehyde" 4: 47%; mp 118-119"; [ a I z 572.7" ~ Ha trans), 3.7 (s, 1, OH); mp 140-142"; mass spectrum (70 ( c 0.5, CHCl3); ir (KBr) 3400, 1805, 1675, 1600, 1530, eV) m l e 358 (M+). 1315, 1245 cm-l; nmr (CDC13) 6 8.6 (d, 1, NH), m at 7.1 Oxidation of 8 with dimethyl sulfoxide and dicyclohex(aromatic and benzene solvate), 6.05 (dd, 1, J1 = 5 , JZ = ylcarbodiimide5 gave, after column chromatography, com11 Hz, H-6), 5.3 (9, 1, H-3), 4.85 (d, 1, J = 5 Hz, H-5), 4.5 (s, 2, CHz), 1.4, 1.45 (s, 6, CH3). This compound seems to pound 9: 20%; mp 148-150"; ir (CHCI3) 3400, 1775, 1690, exist entirely in the ring-closed form since no aldehyde 1600, 1495 cm-l; nmr (CDC13, cephem numbering) 6 8.0absorption is detectable by nmr.1JY4 6.9 (m, aromatic and NH), 6.0 (5, 1, H-4), 5.7 (dd, 1, J1 = "Aldehyde" 4 was reduced to alcohol 5 with sodium bo5, 5 2 = 8.5 Hz, H-7), 5.25 (d, 1, J = 5 Hz, H-6), 5.05 (s, 1, rohydride: 569'0, mp 142-144"; [ a J Z 28.6 5 ~ ( c 1, CHCL); OH), 4.5 (s,2, CHz). mass spectrum, (70 eV) m l e 219 [Mf - SO&Compound 9 was tested for biological activity6 and was (CH&CHzOH]; ir (KBr) 3300-3500, 1780, 1660, 1600, shown to be active against Diplococcus pneumoniae, 0.4;
278 J . Org. Chem., Vol. 39, No. 2, 1974
Streptococcus pyogenes, 1.6; and Staphylococcus aureus, 6.3 (minimum inhibitory concentration in pg/ml). Acknowledgment. This work was assisted financially by a grant from the Sloan Basic Research Fund and by a grant from Bristol Laboratories, Division of Bristol-Myers Co,, Syracuse, N. Y. References and Notes (1) Par! I l l . J . C Sheehan and J. U. Piper, J. Org Chem, 38, 3492 (1973).
Communications (2) J C Sheehan and C A Panetta, J Org Chem , 38,940 (1973) (3) All new compounds gave satisfactory elemental analyses (4) K Heusler, Helv Chim Acta, 55,388 (1972) (5) K E Pfitzner and J G Moffatt, J Amer Chem SOC 85, 3027 (1963) (6) Bristol Laboratories, Division of Bristol-Myers Co , Syracuse, N Y
Department of Chemistry Massachusetts Institute of Technology Cambridge, Massachusetts 02139
John C. Sheehan* Haldean C. Dalzell John M. Greenwood Dagmar R. Ponzi
